Experiments will be conducted during rest, treadmill exercise, and exercise recovery in overnight fasted dogs in which hormone levels and neural outflow are controlled using surgical (pancreatic denervation, pancreatectomy) and pharmacological (adrenergic blockers, somatostatin) techniques. Pathways for hepatic glucose production and hepatic and muscle glucose metabolism will be assessed using arteriovenous difference (liver, limb) and isotopic (3-3H-glucose, U-14C-alanine, U-14C-glucose) techniques. In the first set of experiments we will study the mechanism by which hepatic glucose production is so closely coupled to glucose utilization during moderate-intensity exercise. We will assess the role of pancreatic innervation, fuel supply, and blood glucose levels in controlling changes in glucagon and insulin levels and glucose production during such exercise. The second group of studies will assess the mechanisms by which fuel supply to the working muscle is maintained in the presence of insulin-induced hypoglycemia. The emphasis will be on understanding the mechanism of the accentuated counterregulatory hormone response to insulin-induced hypoglycemia during exercise and how this impacts muscle metabolism. The third set of experiments is designed to determine the regulatory mechanisms that come into play during 'high stress' exercise conditions (high intensity exercise, exercise in poorly- controlled diabetes), in which hepatic glucose production and utilization are no longer closely linked. It is hypothesized that under these conditions hepatic adrenergic drive, instead of changes in glucagon and insulin, is the main stimulus for increasing hepatic glucose output. In addition to hormones and nerves, the glycogen content of the liver is an important determinant of the increase in hepatic glucose production. The final set of experiments will be conducted to ascertain the mechanism by which prior exercise improves the ability of the liver to store glycogen. The role of specific pathways for glucose metabolism in the liver and their regulation by elevated insulin, the hepatic glucose load, and the arterial-portal vein glucose gradient will be assessed during simulated feeding in the post-exercise state. The studies proposed herein will further our understanding of factors that regulate carbohydrate metabolism during and after exercise under physiologic conditions and provide insight into factors that contribute to pathologic conditions.